16 Cycloaddition Rxns 1

Cycloaddition Reactions: Diels-Alder Reaction

D. A. Evans

Chem 206

The Diels-Alder Cycloaddition Reactions http://www.courses.fas.harvard.edu/colgsas/1063 "Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (electronic handout)

Chemistry 206 Advanced Organic Chemistry Lecture Number 16

Cycloaddition Reactions-1 ! Cycloadditions: Introduction ! Ketene Cycloadditions ! The Diels-Alder Reaction

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002, 41, 1668-1698 (electronic handout) Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (electronic handout) Chemistry and Biology of Biosynthetic Diels–Alder Reactions Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42, 3078-3115 (electronic handout)

Reading Assignment for week:

Problem of the Day: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions

Rationalize the sense of asymmetric induction for this Diels-Alder Reaction reported by MacMillan, JACS, 2000, 122, 4243. (pdf)

Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations

O PhCH2

CHO

Pavel Nagorny

+ R

5% catalyst MeOH-H2O

Me

N H Me

X

X

Wednesday, October 25, 2006

Me N

catalyst

CHO R

The Carbonyl Ene Reaction

D.A. Evans

Chem 206

The carbonyl ene reaction is a very powerful transformation that I want to introduce to you. Accordingly, I have prepared a series of problems taken from the Problems Database to familiarize you with this reaction. Problem 210 is provided as an introduction to the FMO analysis for the process. Subsequent problems have the ene reaction imbedded in reaction cascades. Problem 210. Question and Answer. The carbonyl ene reaction is illustrated below. Using FMO analysis, evaluate the transition state of this reaction. Your answer should include: a transition state drawing; clear orbital depictions and HOMOLUMO assignments; an indication of the number of electrons from each segment; and indication of whether the reaction is thermally allowed. H

O Ra

H

O

CH2

O

+

H

Rb

Ra

Rb

H

H

Ra

Rb

Answer Rb

Rb allyl HOMO

bonding

H

Ra

C

H

bonding Ra

O

The ene transition state

O Ra H

H

Rb

bonding

CH2 Rb

H

H

C

Ra O

H

H C

carbonyl LUMO

O

View the ene TS as a 3-component cycloaddition One possible analysis: allyl anion: 4 eProton carbonyl: 2 e[2!s + 2!s +2"s]

6!e- "cycloaddition" suprafacial thermally allowed

Cycloaddition Reactions-1

D. A. Evans

Why does maleic anhydride react easily with 1,3-butadiene, but not with ethylene? So what are the "rules"? O

O

O

! Consider [2 + 2] cycloaddition: Photochemical activation

!*

X

[4+2]

O

LUMO

new HOMO

!*

[2+2]

bonding bonding

Y

Y

X

X

C !

!

C

!

• •

X

C

C

light

C

concerted

C C

C

C

C

C

C

C

C

+ energy

[2+2] Cycloaddition - Examples

! Nomenclature C

suprafacial

!2s

C

antarafacial

!2a

h!

C

C

Using this nomenclature, the Diels-Alder reaction is a !4s

+ !2s cycloaddition Me

+ !2s]

bonding

C antibonding

!2s

C

+ !2s] "forbidden"

Me Me

h!

Me Me

Me

["2s + "2s] Me

Me

Prismane-Der.

C

[!2s + !2a]

bonding

[ !2s

Schäfer, AC 1967, 79, 54.

!2a

C C

Me

Dewar benzene-Derivative

C C

bonding

Me

Me

Me

C

Quadricyclane Dauben, Tet. 1961, 15, 197.

["2s + "2s]

! Consider [2 + 2] cycloaddition: Thermal activation [ !2s

[ !2s

HOMO

!

C +

The frontier orbitals of the reacting species must have the proper symmetries

!2s

!

C

! We also know that the photochemical variant is concerted

!2s

C

O

! The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition heat

+ !2s]

C

light

O

Y

[ !2s

O

O

O

Chem 206

+ !2a] "allowed"

H

must be antarafical for indicated stereochem

TL 1967, 4357, 4723.

Cycloaddition Reactions-2

D. A. Evans

Summary of Ketene Cycloadditions R

R

O

R'

B:

R R'

–ZnCl2

Cl

R

O

O

Electrocyclic Ring Opening

R'

R' O

C O R

R

R

O

H

Cl

R

R'

R

Cl

Zn

Cl

O O

R

O

O

R'

O

Chem 30

R

h!

C

R

or "

R R

O

O

H

C

R

O

R

R'

R

R

O

H R

O

O

R'

Cycloaddition: FMO Analysis

R Y

O

R'

Ketene Preparation

C

B–H

B: R3N

H

R

O

R

R

Antarafacial

R

R Cl

E2 Elimination O

O OR

R

Suprafacial

C O

Cl R

LiNR2

!

R

H

H

Cl

H

O

[!2s!2a]

R

R

C

O

R

O

N

R = -CH=CH2

Y

C O

or !

N2

R'

H

h"

H

Imine

X

X

R

Alkene

Carbonyl

O

R

OR R E1cb Elimination

bonding C O

R

HOMO

R

R

C

bonding

H

H

R

R LUMO

C

R O

Cycloaddition Reactions-3

D. A. Evans

[2+2]: Stepwise Versus Concerted H

H

R

H C R'

C

H

R

H

O

MeO R'

C

Chem 30

O

O

O CMe3

O

R'

R

H

CMe3

2. NBu3, toluene, !

R

R

H

R

least hindered bond rotation

Stepwise

1. (COCl)2, PhH, !

CO2H

O

H

• Very large polar effects • E olefins yield a mixture of cis and trans products

NEt3

H

• Solvent effects observed, but it could merely be a ground state effect

O

C

CH2COCl

• KIE seen for many reactions support stepwise mechanism

O

H

• Calculations show a highly asynchronus transition state. • Stereochemical consequence can be rationalized by stepwise mechanism

Concerted

Cl

• Ketenes add stereoselectively to Z alkenes.

Cl

Cl

Zn

Cl

O

Cl

Cl

Cl

+

C

C

• Z olefins are much more reactive than E olefins

Cl

O

O

Ketene-Alkene [2+2] O

Me

C Me

+

Me

!

Me

Me Me

C

Me

!

+

Me

Me

Fast

Me

Me

O

Me

Me

Me

Ketenes + Aldehydes Afford !-Lactones

O

ab initio Calulations

Me

H

Me

O +

Me 1:2

O

O

Me Me

O

Me

H

H

O

+ 32 kcal/mol

O

Me + Me Me

Me

H Me

C

O

Me C O

Me

Me

C

H Me

C

Me O

Me H

H H

H

38 kcal/mol

path A

C

O

O

H

C

H

H

O

path B

O Pons, J. -M.; et. al. JACS 1997, 119, 3333.

H

H H

H

favored

Me

Cycloaddition Reactions-4

D. A. Evans

Transformations of !-Lactones R2

O

The stepwise mechanism,,,,

R2

" or BF3 -CO2

O

R1

R

R1

R

Most soft Nu attack Csp3

+S

Me2S

O

O

O

R2N

H H

R

N

H

N O

R

conrotatory closure

R

H

R

R'

R'Li (2eq)

R

O

R

(E) Imine ! Cis Product

CuCN

O

N

O

O

O R2N

_

H

R

N

H

N

H

H H

R

R

H

R

C O

Chem 30

O

R R

R

CO2H

Vederas et al JACS 1987, 107, 4649.

(Z) Imine ! Trans Product

H

H

R

The Staudinger Reaction In this process, the illustrated ketene, generated in situ from an acid chloride, undergoes reaction with the indicated substrates to form !lactams in a stereoselective process. When the azo-methine (RN=CHR) geometry in the reactant is (Z) the product stereochemistry is trans (eq 1). In a complementary fashion, the (E) imine affords the cis-substituted product (eq 2). While this transformatlion could be viewed as a [2s+2a] cycloaddition, it is felt that this reaction is stepwise.

H C

H

O conrotatory closure

N

O

S N

O S

H H

S

N R

R

H

H

R

R S

N

H H S N

O

O

There are two contortaory modes. If you control the conrotatory mode, you control the absolute stereochemistry of the reaction:

H R Et3N O

Cl

R

H

H H

R

S N

(Z)

S (1)

N

H N

O

Bn

C O

O O

Ph

H

R R

R

N

(E)

H H

(2) N

O

R

O

Ar

O Et3N

N

N

Cl

Evans, SjogrenTet. Lett. 1985, 26, 3783, 3787. See also Evans, Williams, Tet. Lett. 1988, 29, 5065.

R

O

O H H

O Ar

N

+ Ph

N O

Bn

Ph

H H N

O

diastereoselection > 95:5 80-90% yields

Ar Bn

Cycloaddition Reactions-5

D. A. Evans

Chem 206 Me

Enantioselective Ketene-Aldehyde Cycloaddiitons 1)

O

O

O +

Me

Br

H

i-Pr2NEt

R

R3N

O

O

R

Me3Si

C

N

Al R

O

N

SO2CF3

Aldehyde 2 (R)

catalyst [time (h), temp (°C)]

% yield

% ee 3 (configuration)

5b (8, -40)

91

92 (R)

5a (16, -50)

93

92 (S)

PhCH2CH2—

5a (72, -78)

89

95 (S)

c

CH2CH(CH2)8—

5b (16, -50)

91

91 (S)

d

Me2CHCH2—

5a (24, -50)

80

93 (S)

e

BnOCH2CH2—

5b (16, -40)

90

91 (S)

f

TBDPSOCH2—

5b (16, -40)

74

89 (R)

g

BnOCH2

5a (16, -50)

86

93 (R)

h

Me3C

5a (16, -50)

91

85 (R)

5b (24, -40)

56

54 (R)

b

i

C6H11—

O

EtO2C

EtO2C 3: >99% yield, 92% ee

BnOCH2— PhCH2CH2—

a

O

KF, CH3CN

O

cat. = 5a: R = Me 5b: R = Cl

2+

Me entry

EtO2C 77% yield, 93% ee

i-Pr

N

O O

-78 °C, 24 h

O

PhMe2Si

Bn

F3CO2S

_

CH2

R3NH•Br

i-Pr

H

H

+

N OTf Cu Me3C H2O OH2 CMe3 OTf PhMe2Si OEt 1 mol%, THF, 3Å MS

O

C +

[RCHO • cat.]

O

O N

O

catalyst (10 mol%)

Me

O

O

H N N Cu O R RO OR2

Me

H

Me3Si observed product

O

Me3Si

O

2+

O N

N Cu

Me3C

H2O

OH2

O

R2O

R1 O H C C

Me Me

R1

CMe3

+ 2 CF3SO3– Nelson, S. G.; Peelen, T. J.; Wan, Z. JACS, 1999, 121, 9742-9743

with J. Janey, Org. Lett. 2001, 3, 2125-2128

O

D. A. Evans

The Diels-Alder Reaction

Chem 206

Articles and monographs of Significance

HO

"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf)

H NMe2

O

H Et

H

O

H H

H

Lepicidin

O

Compactin: R = H Mevinolin: R = Me

H

O

Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (pdf)

Et

O

Me

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002, 41, 1668-1698 (pdf)

Chemistry and Biology of Biosynthetic Diels–Alder Reactions Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42, 3078-3115 (pdf)

O

O

(Synthesis) JACS, 1993, 115, 4497

O

H Me

Me

H

O

Me

R

(Biosynthesis) JACS 1985, 107, 3694 Clive, JACS 1988, 110, 6914 Kozikowski, JOC 1987, 52, 3541 O H Keck, JOC 1986, 51, 2487 H Me O Grieco, JACS 1986, 108, 5908 H OMe H Heathcock, JACS 1985, 107, 3731 MeO OMe H Girotra, Tet. Let. 1983, 24, 3687 Hirama, JACS 1982, 104, 4251

Recent Advances in Natural Product Synthesis by Using Intramolecular Diels-Alder Reactions, Tadano et al. Chem Rev. 2005, 105, ASAP (pdf) HN O

Me

! The Reaction:

Me

‡

These natural products could well have incorporated the DA rxn into the biosynthesis Ph

H

H

H H

H

H

Endiandric Acid C

O

H

Me

Et Me

H

ent-FR182877 (WS9885B) J. Antibiotics 2000, 53, 204 TBSO

TBSO

CO2Et Me

H

Me

O

DA Het DA

H

Me

Br H

H

OTBS

CO2H

Endiandric Acid B (Syntheses) Nicolaou, JACS 1982, 104, 5555-5562

OTBS CO2Et

H H

O

H

Ph H

Me

H

HO

Et

Roush JOC 1984, 49, 3429 Nicolaou JOC 1985, 50, 1440 Ley Chem. Commun. 1983, 630

TBSO H

O

OH

H

X-14547A

! Representative natural products displaying the Diels-Alder retron:

HO2C

O COOH

+

Me

H

TBSO

Br

Me

Me

Sorensen, JACS 2003, 125, 5393 Evans, JACS 2003, 125, 13531

H

O Me

Diels-Alder Reaction-Orbital Symmetry Considerations

D. A. Evans The Alder Endo Rule

The following observation illustrates an example of the Alder Rule which will be defined below.

H + H

disfavored

H

Orbital Symmetry Considerations for Diels Alder Reaction If the symmetries of the frontier MO's of reacting partners are "properly matched" the reaction is referred to as "symmetry-allowed". The Diels-Alder reaction is such a case. As illustrated, the HOMO and LUMO of both the diene and dienophile, which in this case are the same, will constructively overlap as indicated in formation of both sigma bonds.

H

favored

"Exo product"

C

"Endo product"

C

Observation: The endo Diels-Alder adduct is formed faster even though the exo product is more stable. There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state. Exo TS

Chem 206

C

‡

C

Energy

Endo TS ‡

C

HOMO-!2

C C

C

C

LUMO-!3

C

C C

C

LUMO-!3

C

HOMO-!2

C

C

Frontier MO Explanation for the Endo Rule C LUMO-!3

C

2

H H

H

! Secondary (transient) orbital overlap can also occcur in the stabilization of certain transition state geometries. Such a transient stabilizing interaction can occur in the endo, but not exo, transition state:

H

C

C

C

C

C HOMO-!2

C

The Other Dimerization Possibility for Butadiene "

Does the possibility for the following concerted dimerization exist?

! Note that the termini only match at one end for the HOMO-LUMO pairing. Hence we say that the symmetry C requirements for the reaction in question are not met. This does not mean that the reaction will not occur, only that the reaction will not be concerted. Such reactions are called "symmetry-forbidden".

C

C HOMO-!2 C C C

C LUMO-!3 C

Diels-Alder Reaction: The Transition Structure

D. A. Evans

Transition State Modelling is Coming of Age

Chem 206

! Lewis Acid Catalysis of the reaction is possible:

‡ +

LUMO2

LUMO1

leading references:

Jorgensen, JACS 1993, 115, 2936-2942 Houk, Jorgensen, JACS 1989, 111, 9172

The Critical Energy Difference:

energy

! The lengths of the forming C–C bonds are Ca. 1.5 times the normal bond distance. This factor comes out of the ab initio work of Jorgensen & Houk

Yates & Eaton, JACS 1960, 82, 4436

E(LUMO1) - E(HOMO2) or E(LUMO2) - E(HOMO1)

HOMO1 HOMO2

Transition Structures of Hydrocarbon Pericyclic Reactions Houk Angew. chem. Int. Ed. 1992, 31, 682-708

Dienophile

Diene

! The closer the two orbitals are in energy, the better they interact ! As !E decreases for the relevant ground state FMOs, rxn rates increase

Ethylene & Butadiene

Vs Butadiene & Acrolein O

O +

+

H

H

LUMO2 LUMO1 LUMO3

E HOMO1

! Diene Reactivity as measured against Maleic anhydride

HOMO2

Me

HOMO3

Me

!E (LUMO3-HOMO1) < !E (LUMO2-HOMO1) log k = 4.96

log k = 2.36 log k = 2.19

log k = 2.12

log k = 1.83

Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807

Rate Acceleration

Lewis acid catalysis not only dramatically increases rates by ca 10+6 it also improves reaction regiochemistry & endo diastereoselectivity

Diels-Alder Reaction: Regiochemistry

D. A. Evans

Chem 206

Here is an interesting problem in reaction design Orientation of Reacting Partners CO2H

CO2H CO2H

CO2H

COX RO

COX

CO2H RO

RO

favored

CO2H

favored

disfavored

4.5 : 01 @ 100 °C

PhS MgBr2

COX Me

Me

COX

COMe

AcO

disfavored

toluene, 120 °C

59 : 41

C6H6, SnCl4, 25 °C

96 : 04

Ni(Raney)

PhS

COMe PhS

AcO

AcO

Trost, JACS 1980, 102, 3554

Me

favored

disfavored

However, what if you need the disfavored product?

Lewis acid catalysis improves orientation COX

COX

disfavored

favored

By employing a removable substituent, it is possible to access the normally disfavored product diastereomer O2N

In general, 1-substituted dienes are more regioselective than their 2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

COMe

RO

NO2 CO2Me

RO

CO2Me

Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity

Lewis acid catalysis improves endo diastereoselection It then can be removed by elimination

H

CO2Me

RO

base

CO2Me

–NO2–

RO

CO2Me

RO

CO2Me

CO2Me H

CO2Me

favored

NO2

disfavored

CH2Cl2, 0 °C

80 : 20

C6H6, SnCl4, 25 °C

95 : 05

NO2

or by reduction Ono, Tet. 1985, 4013 RO

R3SnH

CO2Me O

O

O

H

83%

H

R3SnH 86%

DA Reactions Part II: The Reaction Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

NO2

Me

Ono, Chem. Commun. 1982, 33-34

O2N

Me

H

Me

mixture of ring-fusion isomers

Chem 206

Diels-Alder Reaction: Regiochemistry

D. A. Evans

Instructive Issues of Regiocontrol with Quinone Dienophiles O

O Me

Me

Me Me

O

H

MeOCH2 Cu(BF4)2

CH2OMe

Me

Cl

Cl

0 °C

CN

CH2OMe

H

Cl CN

CN MeO

MeO

O

O

O Me

Me

Me

SnCl4 (-20 °)

95 :5

Sn O Cl4

H

Ph–N

H

O MeO

O

H

25-50 °C

O

selection 80 : 20 MeO

Ratio: 90 : 10

Corey, JACS 1969, 91, 5675

Ratio 50 : 50

!+

O

H

thermal (100 °) BF3•OEt2 (-20 °)

O

O

Me

O

Conditions

Orientation of Reacting Partners controlled by Lewis acid structure Reusch JOC 1980, 45, 5013 F3B

MeO

H

Me

Me

OR

Similar results provided by Stoodley Chem. Comm. 1982, 929

Me

O N–Ph

Ratio

–OH

36 : 64

–Me

83 : 17

–OMe

>97 : 3

Me

OR

OR

O 25-50 °C

O

N–Ph

N–Ph

Kelly Tet. Let. 1978, 4311 O

OMe BF3•OEt2

O

OMe

RO

selection >95 :5

0.4 equiv

OH Me O

Franck, Tet. Lett. 1985, 26, 3187 Franck, JACS 1988,110, 3257

Me

selection >95 :5 OH

O

OMe

O

Me

Me H

! Avoid Eclipsing allylic substituents ! better donor (Me) anti to forming bond

0.5 equiv

Me

R = Me: Ratio; 83 : 17 R = Me3Si: Ratio; 88 : 12

Comments on the Transition State

RO

O

Me

O O

MgI2

OMe

O

Me

Me

RO

OH

Me

! avoid gauche OR interaction

Me PhN O

O

RO H

OR

better than

Me PhN O

O

Diels-Alder Reaction: Selected Problems from the Database

D. A. Evans

Problem 76, Bodwell has disclosed an interesting thermally initiated reaction cascade that was designed to cuminate in a formal synthesis of strychnine(Angew. Chem. Int. Ed 2002, 41, 3261). One of his reported transformations is illustrated below. NCO2Me N

NCO2Me heat, 48 h

N

N

Problem 157. A short reaction sequence that results in the rapid assemblage of the taxane skeleton has been reported by Winkler (Tetrahedron Lett.1995, 36, 687). This transformation is illustrated below wherein intermediate A is subsequently induced to react with divinyl ketone. Provide a concise mechanism for this reaction. For full credit, the relative stereochemical relationships at the indicated stereocenters must be provided.

Problem 86. In 1983 Masamune introduced a new family of chiral controllers for the DielsAlder reaction (J. Org. Chem. 1983, 48, 4441).

Me

ZnCl2 –45 °C

OEt C7H15

(1)

Please provide a mechanism for the reaction shown in equation 1. Be sure to include clear transition state drawings in your answer, and predict the stereochemistry of the major product diastereomer.

C7H15

O

OH

H O OEt

2

OH

HO

H

3

O

C7H15

Problem 778. Boger and co-workers recently reported the synthesis of the indole alkaloid minovine (1). This pivotal transformations leads to the construction of the minovine skeleton. Provide plausible mechanisms for this transformation.

heat

O

Me MeAlCl2

Me

Me

CH2Cl2 Me

H

160 oC

1

Problem 112. In a recent article, Roush reported the highly endo-selective, Lewis acid catalyzed Diels-alder reaction illustrated below (Org. Lett 2001, 3, 957). Using your knowledge of Diels-Alder transition states, draw the transition state of this reaction, and from this drawing, predict the relative stereochemical relationships that are to be anticipated in the product.

O

O

O

MgBr2•Et3N

O

CMe3 exo:endo = 94:6 endo diastereoselection >99:1

Me

O

O

EtO

OH

❊ ❊

❊

+ A

O S

Me

Me Me

Lewis acid

Problem 739. The rapid assembly of the bicyclo[5.3.1]undecane core of penostatin F was recently reported by Barriault and coworkers (Org. Lett. 2004, 6, 1317). In this remarkable transformation dihydropyran 1 is converted to the highly complex tricycle 3 in only two operations. Please provide a detailed mechanism for this reaction sequence. Be sure to indicate all pericyclic reactions.

O

O

O

heat

N

Provide a detailed mechanism for this reaction cascade. Your answer should include threedimensional structures that accurately depict ground and transition state representations.

CMe3

Me

Me

–N2

OH

Chem 206

diastereoselection >99:1

Problem 794. Doering and Rosenthal reported the interesting conversion of Nenitzescu's hydrocarbon (1) to dihydro-naphthalene (2). Provide a mechanistic rationalization for this transformation. (Reference: Doering, W.v.E.; Rosenthal, J.W., JACS 1966, 88, 2078)

Me R

R

300 °C

1

2